- RA is an autoimmune disease with a prevalence of 1% in western Europe and America, but with a variable frequency in other ethnic groups. The genetic susceptibility to develop RA is associated with the human immune response genes HLA-DR4. This association is thought to be due in part to an uncontrolled activation of CD4+ T cells by autoantigenic protein molecules derived from synovial joints. This proposal suggests using HLA-DR trg mice to develop a peptide-based immunomodulatory treatment aiming specifically at controlling this process. HLA-DRB*0401 and *0405 trg mice, both associated with susceptibility to RA, would be used to determine the immunogenic peptide epitopes of human autoantigenic proteins by producing antigen-specific T cell hybridomas after immunization of these mice with the human proteins. Two such human joint proteins, human collagen type II (hCII), a major constituent of synovial cartilage, and human chondrocyte glycoprotein 39 (HCgp39) can induce arthritis in the *0401 trg mouse. Forty percent of RA patients' T cells can respond to HCgp39. The HLA-DR4 trg mouse model could be an important in vivo model for testing new peptide-based immunomodulatory treatments for RA patients. Such peptides could be used to develop a narrow antigen-specific tolerance by inducing anergy or Th1/Th2 skewing, which would be much better tolerated by patients than the often very toxic treatments for RA that we know of.